impaginato piccolo - Società Italiana di Parassitologia (SoIPa)

FP6 project ANTIMAL. At the same time, the group of
D. Monti of CNR-ISTM-Milano is involved in the
development of novel synthetic approaches and combinatorial
synthesis for a rapid, cheap, clean and scalable
route to 4-aminoquinolines. They first employed the
microwave assisted reactions and subsequently they
applied “click chemistry” for the efficient conversion of
the commercially available 4,7-dichloroquinoline into a
library of aminoquinolines in high yields and purities,
in a very short time with no need for further purification
steps. They also investigated the trichlorotriazine
as core scaffold for the synthesis of multivalent antimalarial
agents: they obtained a series of compounds
that exibit good reactivity in vitro against CQ-R strains
(Melato, Coghi et al. 2007; Melato, Prosperi et al.
2008).
Rational design of new chemical entities.
The research activity of the NatSynDrugs unit
(www.natsyndrugs.org, G. Campiani, University of
Siena and C. Fattorusso University Federico II, Naploli)
is focused on the identification of new low cost, safe
drugs for the treatment of drug resistant parasites. The
synthetic strategy is based on the rational design of new
compounds able to coordinate metals, haemoglobin
iron in particular, in the reducing milieu of Pf (redox
milieu -250 mV), thus producing radical species selectively
toxic for the parasite (altering Pf fragile redox
equilibrium). Several classes of new compounds with a
common metal-mediated mechanism of action have
been synthesised and some of them are characterized
by (i) potent antimalarial activity in vitro against CQ-R
strains of Pf; (ii) lack of in vitro cytotoxicity against
normal cells; (iii) a promising in vivo activity against
both P. berghei and P. chabaudi in mice (Gemma,
Campiani et al. 2007; Gemma, Kukreja et al. 2007;
Fattorusso, Campiani et al. 2008; Gemma, Campiani et
al. 2008; Gemma, Kukreja et al. 2008). Some of these
molecules have been selected as leads compounds for
further in vivo studies and have been patent protected.
(Campiani G., Gemma S. et al. (2007) US No.
60/890,862 EP2007/052174, EP2007/052176)
Evaluation in vitro against whole parasites (hit selection)
and in vivo in animal models (lead selection).
All the synthetic compounds and isolated natural products
have been assayed in vitro against P. f. strains with
a different resistance phenotype by D. Taramelli group,
University of Milan. A spectrophotometric chemosensitivity
assay based on the evaluation of P.f pLDH has
been used. Molecules with an IC50